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- Title
CYP3A5 mediates bioactivation and cytotoxicity of tetrandrine.
- Authors
Tian, Ye; Shen, Shuijie; Jiang, Yan; Shen, Qi; Zeng, Su; Zheng, Jiang
- Abstract
Tetrandrine is a diaryl ether-type bisbenzylisoquinoline alkaloid and has shown multiple pharmacological activities. Our early work demonstrated that tetrandrine produced acute pulmonary toxicity and that tetrandrine was biotransformed to a quinone methide-derived metabolite mediated by CYP3A enzymes. The formation of the reactive intermediate is suggested to be responsible for the pulmonary toxicity induced by tetrandrine. In the present study, a WI-38-based Cyp3a5 transgenic cell line (WI-38/ Cyp3a5) was established to investigate the role of CYP3A5 in tetrandrine-induced cytotoxicity. The transgenic cells were found to be more susceptible to the cytotoxicity of tetrandrine than the wild-type cells (WI-38/Vector). WI-38/ Cyp3a5 cells showed higher cellular ROS levels, higher LDH activities in culture media, but lower cellular GSH contents than those observed in WI-38/Vector cells after exposure to tetrandrine. And severer apoptosis were observed in WI-38/ Cyp3a5 cells after treatment with tetrandrine: WI-38/ Cyp3a5 cells had higher proportion of early and late apoptotic cells, higher expression levels of caspase-3, but lower level of Bcl-2 than WI-38/Vector cells. This study provided strong evidence that CYP3A5 participated in tetrandrine-induced cytotoxicity.
- Subjects
TETRANDRINE; BIOTRANSFORMATION (Metabolism); QUINONE methides; DIARYL compounds; METABOLITES; CULTURE media (Biology); THERAPEUTICS
- Publication
Archives of Toxicology, 2016, Vol 90, Issue 7, p1737
- ISSN
0340-5761
- Publication type
Article
- DOI
10.1007/s00204-015-1584-8